"The U.S. Food and Drug Administration announced today that it has approved the influenza vaccine formulation for the 2011-2012 vaccine that will be used by the six manufacturers licensed to produce and distribute influenza vaccine for the United "...
Mechanism of Action
Influenza illness and its complications follow infection with influenza viruses. Global surveillance of influenza identifies yearly antigenic variants. For example, since 1977, antigenic variants of influenza A (H1N1 and H3N2) viruses and influenza B viruses have been in global circulation. Specific levels of hemagglutination-inhibition (HI) antibody titer post-vaccination with inactivated influenza virus vaccines have not been correlated with protection from influenza illness but the HI antibody titers have been used as a measure of vaccine activity. In some human challenge studies, HI antibody titers of ≥ 1:40 have been associated with protection from influenza illness in up to 50% of subjects.1,2 Antibody against one influenza virus type or subtype confers little or no protection against another virus. Furthermore, antibody to one antigenic variant of influenza virus might not protect against a new antigenic variant of the same type or subtype. Frequent development of antigenic variants through antigenic drift is the virological basis for seasonal epidemics and the reason for the usual incorporation of one or more new strains in each year's influenza vaccine. Therefore, inactivated influenza vaccines are standardized to contain the hemagglutinins of strains (i.e., typically 2 type A and 1 type B), representing the influenza viruses likely to circulate in the United States in the upcoming winter.
Annual revaccination with the current vaccine is recommended because immunity declines during the year after vaccination, and because circulating strains of influenza virus change from year to year.3
Efficacy Against Culture-Confirmed Influenza
The efficacy of FLUARIX was evaluated in a randomized, double-blind, placebo-controlled study conducted in 2 European countries during the 2006-2007 influenza season. Efficacy of FLUARIX, containing A/New Caledonia/20/1999 (H1N1), A/Wisconsin/67/2005 (H3N2), and B/Malaysia/2506/2004 influenza strains, was defined as the prevention of culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains, compared with placebo. Healthy subjects 18 to 64 years of age (mean 39.9 years) were randomized (2:1) to receive FLUARIX (N = 5,103) or placebo (N = 2,549) and monitored for influenza-like illnesses (ILI) starting 2 weeks post vaccination and lasting for approximately 7 months. In the overall population, 60% of subjects were female and 99.9% were white. Culture-confirmed influenza was assessed by active and passive surveillance of ILI. Influenza-like illness was defined as at least one general symptom (fever ≥ 100°F and/or myalgia) and at least one respiratory symptom (cough and/or sore throat). After an episode of ILI, nose and throat swab samples were collected for analysis; attack rates and vaccine efficacy were calculated (Table 4).
Table 4: Attack Rates and Vaccine Efficacy Against Culture-Confirmed
Influenza A and/or B in Adults 18 to 64 Years of Age (Total Vaccinated Cohort)
|N||N||Attack Rates (n/N) %||Vaccine Efficacy|
|Antigenically Matched Strainsa|
|All Culture-Confirmed Influenza (Matched, Unmatched, and Untyped)c|
|a There were no vaccine matched
culture-confirmed cases of A/New Caledonia/20/1999 (H1N1) or B/Malaysia/2506/2004
influenza strains with FLUARIX or placebo.
b Vaccine efficacy for FLUARIX exceeded a pre-defined threshold of 35% for the lower limit of the 2-sided 95% CI.
c Of the 22 additional cases, 18 were unmatched and 4 were untyped; 15 of the 22 cases were A (H3N2) (11 cases with FLUARIX and 4 cases with placebo).
In a post-hoc, exploratory analysis by age, vaccine efficacy (against culture-confirmed influenza A and/or B cases, for vaccine antigenically matched strains) in subjects 18 to 49 years of age was 73.4% (95% CI: 59.3, 82.8) [number of influenza cases: FLUARIX (n = 35/3,602) and placebo (n = 66/1,810)]. In subjects 50 to 64 years of age, vaccine efficacy was 13.8% (95% CI: -137.0, 66.3) [number of influenza cases: FLUARIX (n = 14/1,501) and placebo (n = 8/739)]. As the study lacked statistical power to evaluate efficacy within age subgroups, the clinical significance of these results is unknown.
Adults: In a randomized, double-blind, placebo-controlled study conducted in healthy subjects 18 to 64 years of age (mean 39.1 years) in the United States, the immune responses to each of the antigens contained in FLUARIX were evaluated in sera obtained 21 days after administration of FLUARIX (N = 745) and were compared to those following administration of a placebo vaccine (N = 190). In the overall population, 54% of subjects were female and 80% were white. For each of the influenza antigens, the percentage of subjects who achieved seroconversion, defined as at least a 4-fold increase in serum hemagglutination-inhibition (HI) titer over baseline to ≥ 1:40 following vaccination, and the percentage of subjects who achieved HI titers of ≥ 1:40 are presented in Table 5. The lower limit of the 2-sided 95% CI for the percentage of subjects who achieved seroconversion or an HI titer of ≥ 1:40 exceeded the pre-defined lower limits of 40% and 70%, respectively.
Table 5: Rates With HI Titers ≥ 1:40 and Rates of Seroconversion
to Each Antigen Following FLUARIX or Placebo (21 Days After Vaccination) in
Adults 18 to 64 Years of Age (ATP Cohort)
|% With HI Titers ≥ 1:40||FLUARIXa
|A/New Caledonia/20/99 (H1N1)||54.8
|A/New Caledonia/20/99 (H1N1)||59.6
|HI = hemagglutination-inhibition; ATP = according-to-protocol;
CI = Confidence Interval. ATP cohort for immunogenicity included subjects
for whom assay results were available after vaccination for at least one
study vaccine antigen.
a Results obtained following vaccination with FLUARIX manufactured for the 2004-2005 season.
b Seroconversion defined as at least a 4-fold increase in serum titers of HI antibodies to ≥ 1:40.
In a randomized, single-blind, active-controlled US study, immunological non-inferiority of FLUARIX (N = 923) was compared with FLUZONE (N = 922), a US-licensed trivalent, inactivated influenza virus vaccine (Sanofi Pasteur SA). Subjects 18 to 64 years and ≥ 65 years of age were evaluated for immune responses to each of the vaccine antigens 21 days following vaccination [see Use In Specific Populations]. In the overall population, 59% of subjects were female and 91% were white. The co-primary immunogenicity endpoints were geometric mean titers (GMTs) of serum HI antibodies and the percentage of subjects who achieved seroconversion, defined as at least a 4-fold increase in serum HI titer over baseline to ≥ 1:40, following vaccination. The primary immunogenicity analyses were performed on the According-to-Protocol (ATP) cohort which included all eligible and evaluable subjects with results of at least one serological assay. For each of the influenza antigens, the GMTs and the percentage of subjects who achieved seroconversion are presented in Table 6. FLUARIX was non-inferior to the comparator influenza vaccine based on antibody GMTs (upper limit of the 2-sided 95% CI for the GMT ratio [comparator influenza vaccine/FLUARIX] ≤ 1.5) and seroconversion rates (upper limit of the 2-sided 95% CI on difference of the comparator influenza vaccine minus FLUARIX ≤ 10%).
Table 6: Immune Responses 21 Days After Vaccination With
FLUARIX Compared With Comparator Influenza Vaccine in Adults ≥ 18 Years of
Age (ATP Cohort)
|GMT (95% CI)||FLUARIX
|Comparator Influenza Vaccine
N = 846-854
|Pre-vaccination||Post-vaccination||Pre- Post-vaccination vaccination|
|Seroconversiona (95% CI)||Post-vaccination||Post-vaccination|
|A/New Caledonia/20/99 (H1N1)||45.7
|A/New York/55/2004 (H3N2)||67.1
Comparator influenza vaccine manufactured by Sanofi Pasteur SA. ATP = according-to-protocol;
GMT = geometric mean antibody titer; CI = Confidence Interval; H1 = A/New Caledonia/20/99
(H1N1); H3 = A/New York/55/2004 (H3N2) for FLUARIX and A/California/7/2004 (H3N2)
for comparator influenza vaccine; B = B/Jiangsu/10/2003. ATP cohort included
all eligible and evaluable subjects with results of at least one serological
a Seroconversion defined as at least a 4-fold increase in serum titers of HI antibodies to ≥ 1:40.
Children: The immune response of FLUARIX was compared to FLUZONE, a US-licensed trivalent, inactivated influenza virus vaccine (Sanofi Pasteur SA), in a single-blind, randomized study in a subset of children 6 months to < 5 years of age (Study 005). The immune responses to each of the antigens contained in FLUARIX formulated for the 2006-2007 season were evaluated in sera obtained after 1 or 2 doses of FLUARIX (N = 426) and were compared to those following administration of the comparator influenza vaccine (N = 445). Further details on the clinical study design and demographic information have been previously described [see ADVERSE REACTIONS].
Non-inferiority of the immune response for FLUARIX to comparator influenza vaccine for subjects 6 months to < 5 years of age was not demonstrated mainly due to lower antibody response to FLUARIX compared to the comparator influenza vaccine in subjects 6 months to < 3 years of age. In subjects 3 years to < 5 years of age, FLUARIX met at least one of the pre-specified criteria for demonstration of non-inferiority (GMT and seroconversion rate) for the influenza A strains but not for the influenza B strain. Seroconversion rates and the percentage of subjects with HI titers ≥ 1:40 were analyzed as secondary endpoints. In subjects 3 years to < 5 years of age, the lower limit of the 95% Confidence Interval of the seroconversion rate for FLUARIX or the comparator influenza vaccine exceeded 40% for all 3 strains; also in this age group, the lower limit of the 95% Confidence Interval of the rate with HI titer ≥ 1:40 for FLUARIX or the comparator influenza vaccine exceeded 70% for both A strains (Table 7).
Table 7: Rates With HI Titers ≥ 1:40 and Rates of Seroconversion
to Each Antigen Following FLUARIX or Comparator Influenza Vaccine in Children
3 Years to < 5 Years of Age (ATP Cohort)
|% with HI titers ≥ 1:40||FLUARIXa % (95%CI)||Comparator Influenza Vaccineb % (95%CI)|
N = 220
N = 220
N = 220
N = 221
|A/New Caledonia||17.3 (12.5, 22.9)||81.8 (76.1, 86.7)||20.5 (15.3, 26.4)||85.5 (80.2, 89.9)|
|A/Wisconsin||59.5 (52.7, 66.1)||88.2 (83.2, 92.1)||55.5 (48.6, 62.1)||93.7 (89.6, 96.5)|
|B/Malaysia||13.6 (9.4, 18.9)||55.0 (48.2, 61.7)||11.8 (7.9, 16.8)||58.4 (51.6, 64.9)|
|A/New Caledonia||72.7 (66.3,78.5)||72.3 (65.9,78.1)|
|A/Wisconsin||70.9 (64.4,76.8)||70.5 (64.0,76.4)|
|B/Malaysia||53.2 (46.4,59.9)||55.5 (48.6,62.1)|
|HI = hemagglutination inhibition; ATP = according
to protocol; CI = Confidence Interval.
a Results obtained following vaccination with FLUARIX manufactured for the 2006–2007 season.
b US-licensed trivalent, inactivated influenza virus vaccine (Sanofi Pasteur SA) without preservative manufactured for the 2006-2007 season.
c Seroconversion defined as at least a 4-fold increase in serum titers of HI antibodies to ≥ 1:40.
1. Hannoun C, Megas F, Piercy J. Immunogenicity and protective efficacy of influenza vaccination. Virus Res. 2004;103:133-138.
2. Hobson D, Curry RL, Beare AS, et al. The role of serum haemagglutination-inhibiting antibody in protection against challenge infection with influenza A2 and B viruses. J Hyg Camb. 1972;70:767-777.
3. Centers for Disease Control and Prevention. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 2010;59(RR-8):1-62.
Last reviewed on RxList: 1/10/2012
This monograph has been modified to include the generic and brand name in many instances.
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